About one third of the world’s population (2 billion people) have been infected by HBV, confirmed by anti-HBV antibodies (past HBV infection), and approximately 240 million people are HBsAg positive (overt carriers), with a high variability of the endemicity levels.

The prevalence of HBsAg is decreasing worldwide, mainly due to universal vaccination programs. Nevertheless, migration of HBV infected individuals from high to low endemic areas could further modify the overall picture of HBV infection, particularly with an increase of primary infection in unvaccinated adults.

HBV is a small, enveloped, hepatotropic, non-cytopathic virus, which may persist in the infected cell without major alteration of cellular homeostasis. The small viral genome (3.2 kb) is a partially double-stranded, relaxed-circular (rc) DNA with a compact organization and four partially overlapped open reading frames encoding seven proteins. At variance with Hepatitis C Virus (HCV), the major steps of the viral life cycle, with the exception of reverse transcription of the pregenomic RNA into HBV-DNA, are mediated by cellular receptors, proteins, or enzymes. Thus, the interaction of the virus with the hepatocyte is pervasive and complex and could make it difficult to identify molecules acting exclusively on the virus machinery.

The interplay between the virus and the host’s immune system determines the outcome of HBV infection: (a) in primary resolving infection, the timely and synergistic response of both the innate and adaptive immune system achieves an effective control of the infection, inducing a robust adaptive T cell reaction (with cytolytic and noncytolytic antiviral effects) and the production by B cells of neutralizing antibodies, preventing the spread of the virus; (b) in chronic infection, HBV-specific T cell function appears to be impaired.

Albeit the major alterations of the immune response, the interaction between HBV and host immune system appears highly dynamic, and about 60% of chronic carriers will spontaneously achieve the control of HBV infection and resolve chronic hepatitis with transition to the phase of Hepatitis B e Antigen (HBeAg) negative infection [1].

The natural history of chronic HBV infection has been schematically divided into five phases according to the two main characteristics, infection and hepatitis [2]:

HBeAg-positive CHB (previously termed “immune tolerant” phase) is characterised by serum HBeAg and very high levels of HBV DNA, while liver necroinflammation or fibrosis are minimal or absent, in absence of other causes of liver damage.

HBeAg-positive CHB is characterised by the presence of serum HBeAg, high levels of HBV DNA, and moderate or severe liver necroinflammation, eventually associated with fibrosis. ALT is usually elevated.

HBeAg-negative chronic HBV infection (previously termed “inactive carrier” phase) is classically characterised by serum anti-HBe, low (<2000 IU/mL) HBV DNA, quantitative HBsAg levels (<1000 IU/mL), and absent or minimal hepatic necroinflammatory activity, in absence of other causes of liver damage. In the classical phase 3, HBsAg loss and/or seroconversion may occur spontaneously in about 1–3% of cases per year. However, some subjects can be attributed to a “grey zone” (higher HBV DNA and/or quantitative HBsAg levels with persistent normal ALT). These anti-HBe-positive carriers without biochemical and histologic evidence of liver disease seldom progress to HBeAg-negative CHB and more frequently remain in this phase or show a further reduction of viral load [3].

HBeAg-negative CHB is characterised by the presence serum anti-HBe with persistent or fluctuating viremia. The liver histology shows necroinflamation and fibrosis. ALT fluctuates or is persistently elevated. Spontaneous disease resolution is rare.

The HBsAg-negative phase is characterised by serum negative HBsAg and positive anti-HBc, with or without detectable anti-HBs. Serum HBV-DNA is usually undetectable, whereas covalently closed circular DNA (cccDNA) can be detected in the liver. Viral induced liver disease is absent. Immunosuppression may lead to HBV reactivation in Occult B Infected patients (OBI) [4].

The treatment of HBV infection is indicated for phase 1 in order to induce anti-HBe seroconversion, and for phases 2 and 4, characterized by chronic hepatitis. However, phases 3 and 5, in absence of chronic hepatitis and significant staging, should be treated with antivirals only in cases of high risk (>10%) of clinical reactivation in immunosuppresed patients [5].

Antiviral therapy is aimed to prevent progression of chronic hepatitis and cirrhosis or reactivation in immunocompromised patients. In immunocompetent patients, two different therapeutic approaches can be used to switch off disease activity: (1) curative, aimed to induce a change in the host–virus equilibrium, from pathogenic to nonpathogenic with a time-limited treatment able to obtain a persistent off-therapy control of HBV replication; (2) suppressive, based on the suppression of viral replication with continuous antiviral treatment.

Pegylated interferon (Peg-IFN) is the major player of the curative strategy; however, only 20–30% of the patients achieve a sustained virologic response (SVR), and it is contraindicated in the majority of immunocompromised patients.

In the suppressive strategy, the long-term (frequently life-long) treatment is based on nucleos(t)ide analogue (NA) drugs that are direct inhibitors of viral polymerase. Nevertheless, NA do not directly act on cccDNA and therefore do not promote the clearance of HBV infection; their discontinuation is associated with viral replication recurrence in the majority of patients. For this reason, at present, NA are usually maintained overtime in HBeAg-positive patients without anti-HBe seroconversion and in anti-HBe positive phase 3 patients without HBsAg clearance.

In the last 20 years, many drugs have been used for the antiviral treatment of HBV: firstly Lamivudine (LAM), then adefovir dipivoxil (ADV) and telbivudine (TBV), and more recently, tenofovir disoproxil fumarate (TDF) and entecavir (ETV), the third generation of antivirals characterized by high antiviral efficacy and high genetic barrer, with consequent clinical improvement and reduction of liver transplantation need ^[6][7][8][6,7,8].

The impact of the antiviral therapy on HCC in cirrhotics has been long debated. Recently, better results have been described with ETV and TDF. A higher efficacy of TDF in the prevention of HCC has been recently reported, particularly by Asian authors, but it remains controversial ^[9][10][9,10].

There are multiple novel antivirals targeting different steps in the HBV life cycle currently in development. The aim of these drugs is the complete cure of the infection in analogy with HCV infection, and not only suppression. The final goal should be the control (functional cure) or the eradication of the infection (complete cure) [11] (Table 1).

The different mechanisms of action of new anti-HBV therapies, mainly in phase II trials, are shown below [12]:

Identification of the Sodium Taurocholate Co-transporting Polypeptide (NTCP) expressed on the hepatocyte membrane has allowed the development of entry inhibitors, which are able to stop HBV and HDV infection of naive hepatocytes during the primary inoculation or the reinfection. Myrcludex B (Bulevertide) and Cyclosporine have exhibited this antiviral activity. Bulevirtide was recently registered in the US and Europe and is now available in clinical practice and in clinical trials as monotherapy or in combination with Peg-IFN.

Nucleocapsid assembly modulators are able to stop HBV core proteins, which are essential for HBV genome packaging.

Post-transcriptional control inhibitors (RNAi or oligonucleotides) can directly target HBV transcripts and induce their degradation, resulting in gene silencing.

HBsAg release inhibitors (Nucleic Acid Polymers) block the release of subviral HBsAg particles. Pilot studies performed in HBV and HDV patients using these drugs combined with TDF and Peg-IFN have been published in recent years with promising results ^[13][14][15][13,14,15]. However, all these studies described a hepatitis flare, clinically significant in some cases, preliminary to the therapeutic response.

Therapeutic approaches aimed at suppressing cccDNA synthesis by small molecules are currently under way, but so far no clinical trials using these innovative drugs called cccDNA targets have been completed.

Patients affected by chronic HBV hepatitis usually show immunologic dysfunction, suggesting a combined cure strategy. Immunomodulation can be induced by interferons, Toll-like receptor agonists, checkpoint inhibitors, and therapeutic vaccines.

In conclusion, chronic HBV infection causes significant morbidity and mortality globally. Long term suppressive therapy with NAs showed a dramatic impact on the evolution of liver disease and liver-related complications. However, the need in many cases for prolonged therapy has stimulated the research of new strategies searching for a functional or complete cure of HBV disease, able to eradicate the infection in analogy with HCV. Unfortunately, HCV is an “easier” virus, without a nuclear replicative phase; the inhibition of cccDNA formation is the crucial challenge that should be addressed by the novel drugs, with an optimal safety profile similar to that of currently used NAs.